H. Köhler

Die Elimination von Hydroxyäthylstärke 200/0,5, Dextran 40 und Oxypolygelatine

SummaryAfter withdrawal of 400 ml whole blood and subsequent infusion of 500 ml of a colloidal plasma substituent, the intravascular and renal colloid elimination was investigated in 40 test subjects. The individual colloidal solutions could no longer be demonstrated in the intravascular space after the following times: 10% hydroxyethyl starch 200/0.5 (anthrone method) after six weeks, 10% dextran 40 (anthrone method) after two weeks, 6% hydroxyethyl starch 200/0.5 (anthrone method) after four weeks and 5.5% oxypolygelatine (hydroxyproline method) after two days.Colloidal plasma substitutes are polydisperse solutions with various molecular weights and degree of hydroxyethylation and therefore, also have a large number of different elimination constants. With repeated application, the intravascular colloid concentration shifts in favour of the molecules with a longer half life which are difficult to eliminate. The elimination of the clinically employed dextran 40 and oxypolygelatine solution could be best described with an open two-compartment model. As a result of its greater heterogeneity, the elimination of the moderately high molecular weight hydroxyethyl starch 200/0.5 could only be characterized approximately even assuming three elimination constants. In the first four days, the hydroxyethyl starch 200/0.5 was more rapidly eliminated compared to dextran 40. However, subsequently a very much lower elimination from the intravascular space was found for about 3% of the administered hydroxyethyl starch 200/0.5. Oxypolygelatine was eliminated especially rapidly. Accordingly, the greatest renal clearance was found for oxypolygelatine, which showed a close relation to the molecular weight. On the other hand, a rapid elimination simultaneously is followed by a correspondingly lower volume effect.ZusammenfassungNach Entzug von 400 ml Vollblut und anschließender Infusion von 500 ml eines kolloidalen Plasmaersatzmittels wurde bei 40 Probanden die intravasale und renale Kolloidelimination untersucht. Die einzelnen kolloidalen Lösungen waren nach folgenden Zeiträumen nicht mehr im Intravasalraum nachweisbar: 10% Hydroxyäthylstärke 200/0,5 (Anthron-Methode) nach 6 Wochen, 10% Dextran 40 (Anthron-Methode) nach 2 Wochen, 6% Hydroxyäthylstärke 200/0,5 (Anthron-Methode) nach 4 Wochen und 5,5% Oxypolygelatine (Hydroxyprolin-Methode) nach-2 Tagen.Kolloidale Plasmaersatzmittel stellen polydisperse Lösungen mit unterschiedlichem Molekulargewicht und Hydroxyäthylierungsgrad und deshalb auch mit einer Vielzahl unterschiedlicher Eliminationskonstanten dar. Bei wiederholter Applikation verschiebt sich die intravasale Kolloidkonzentration zu Gunsten der schwer eliminierbaren Moleküle mit längerer Halbwertzeit. Die Elimination der klinisch eingesetzten Dextran 40- und Oxypolygelatine-Lösung ließ sich am besten mit einem offenen 2-Kompartiment-Modell beschreiben. Die Elimination der mittelmolekularen Hydroxyäthylstärke 200/0,5 war als Ausdruck ihrer größeren Heterogenität auch unter Annahme von drei Eliminationskonstanten nur näherungsweise zu charakterisieren. In den ersten 4 Tagen wurde die Hydroxyäthylstärke 200/0,5 im Vergleich zu Dextran 40 rascher eliminiert. Anschließend aber fand sich für ca. 3% der zugeführten Hydroxyäthylstärke 200/0,5 eine wesentlich langsamere Elimination aus dem Intravasalraum. Besonders schnell wurde Oxypolygelatine ausgeschieden. Dementsprechend fand sich für Oxypolygelatine die größte renale Clearance, die eine enge Beziehung zum Molekulargewicht zeigte. Andererseits bedeutet eine rasche Elimination gleichzeitig eine entsprechend geringere Volumenwirkung.

TGF-β Regulates Airway Responses Via T Cells

Allergic asthma is characterized by airway hyperreactivity, inflammation, and a Th2-type cytokine profile favoring IgE production. Beneficial effects of TGF-β and conflicting results regarding the role of Th1 cytokines have been reported from murine asthma models. In this study, we examined the T cell as a target cell of TGF-β-mediated immune regulation in a mouse model of asthma. We demonstrate that impairment of TGF-β signaling in T cells of transgenic mice expressing a dominant-negative TGF-β type II receptor leads to a decrease in airway reactivity in a non-Ag-dependent model. Increased serum levels of IFN-γ can be detected in these animals. In contrast, after injection of OVA adsorbed to alum and challenge with OVA aerosol, transgenic animals show an increased airway reactivity and inflammation compared with those of wild-type animals. IL-13 levels in bronchoalveolar lavage fluid and serum as well as the number of inducible NO synthase-expressing cells in lung infiltrates were increased in transgenic animals. These results demonstrate an important role for TGF-β signaling in T cells in the regulation of airway responses and suggest that the beneficial effects observed for TGF-β in airway hyperreactivity and inflammation may be due to its regulatory effects on T cells.

Macroamylasaemia after treatment with hydroxyethyl starch

Abstract. After infusion of 500 ml of 6% hydroxyethyl starch into fifty‐four patients an increase of serum amylase was observed which in fifty‐one cases exceeded the upper limit of normal (190 U/l). In most cases serum amylase reached twice the basal value. Renal function influenced the duration of the increase in serum amylase, but not the maximum increase (201±15 U/l; mean±SEM). In patients with advanced renal failure (glomerular filtration rate (GFR) = 2–10 ml/min) serum amylase was still markedly elevated after 72 h (298±24 U/l; mean±SEM). In patients with normal renal function (GFR>90 ml/min) serum amylase decreased to 183±40 U/l (mean±SEM) within 72 h without reaching basal values. After infusion of HES no changes were observed in serum lipase or in amylase or lipase activities in duodenal secretion. Amylase excretion in the urine decreased. The assumption of a macroamylasaemia caused by formation of an HES‐amylase complex was confirmed by gel filtration. The elimination from plasma of this high molecular enzyme‐substrate complex is slow and causes hyperamylasaemia. In no case was the macroamylasaemia associated with signs or symptoms. An awareness of this causal relationship seems to be important, to avoid the erroneous diagnosis of a pancreatic disease.

[Pharmacocinetics and dosage of dextran 40 in relation to renal function (author's transl)].

Summary36 patients with different renal function (GFR=0.5−142 ml/min) received 500 ml of 10% dextran 40 (Rheomacrodex®). The relative distribution volume proved to be 10.2±2.21/100 kg. Dextran 40 half life time and renal function are correlated mathematically as a power function. In patients with normal renal function (GFR>90 ml/min) we determined a dextran 40 half life time of 573±138 min and a 12 hour urinary recovery of 48%. In contrast to that a glomerular filtration rate below 10 ml/min prolongs the half-life five times to a value of 2591±1022 min and reduces the urinary elimination to 4% per 12 hours. In patients with a clearance between 30 and 142 ml/min no essential changes of half life time and urinary elimination can be observed. To those patients dextran 40 can be applied in the common dosage. Contrary to that a glomerular filtration rate below 30 ml/min leads to a prolonged elimination and consequently a different dosage has to be applied.Zusammenfassung36 Patienten mit unterschiedlicher Nierenfunktion (GFR zwischen 0,5–142 ml/min) erhielten 500 ml 10%iges Dextran 40 (Rheomacrodex®). Dabei ergab sich ein relatives Verteilungsvolumen von 10,2±2,2 1/100 kg. Die Eliminationshalbwertzeiten von Dextran 40 stehen mit der Nierenfunktion (51 Cr-EDTA-Clearance) in einem Zusammenhang, der sich rechnerisch am besten durch eine Potenzfunktion darstellen läßt. Patienten mit normaler Nierenfunktion (GFR über 90 ml/min) haben eine Eliminationshalbwertzeit von 573±138 min und eine 12 Std-Recovery im Urin von 48%. Ein Glomerulusfiltrat unter 10 ml/min führt dagegen zur Verlängerung der Halbwertzeit auf das Fünffache (Dextran 40-HWZ=2591±1022 min) und zum Rückgang der 12 Std-Recovery auf 4%. Im Clearancebereich zwischen 30 und 142 ml/min bleiben Eliminationshalbwertzeit und Urinausscheidung im wesentlichen konstant. Dextran 40 kann deshalb bei diesen Patienten nach den bekannten Regeln dosiert werden. Bei glomerulären Filtrationswerten unter 30 ml/min ist jedoch mit einer gestörten Elimination zu rechnen. Aus der veränderten Dextran 40-Ausscheidung im Urin und aus den Eliminationshalbwertzeiten ergeben sich Dosierungsrichtlinien, die diskutiert und tabellarisch aufgeführt werden.

Cerebral toxicity of penicillins in relation to their hydrophobic character

SummaryThe neurotoxic effects of ticarcillin, methicillin, phenthicillin, oxacillin, cloxacillin and dicloxacillin were studied in the conscious rabbit. During and after intravenous administration of 1.2 and 2.4 g/kg, resp., over 50 min the blood concentrations of the drugs were determined and the neurotoxicity assessed by continuous recording of the electroencephalogram. The hydrophobia of the penicillins was characterized by determination of their partition coefficients between isobutanol and buffer solution pH 7.4. The penicillins showed quite different neurotoxic properties. A close correlation (r=0.928) was found between the neurotoxic potency of the penicillins and their partition coefficients. With increasing hydrophobia the neurotoxic potency increased in the following sequence: Ticarcillin, methicillin, oxacillin, phenethicillin, cloxacillin, dicloxacillin. It can be concluded, therefore, that determination of the partition coefficient of a penicillin gives valuable information on the neurotoxicity to be expected. The introduction of a neurotoxicity quotient revealed that penicillins may be divided into two groups: less neurotoxic penicillins with a partition coefficient below 1.0 and highly neurotoxic penicillins with a partition coefficient above 1.0.

Interaction of hemoglobin with band 3: a review.

SummaryThe oxygen transport protein hemoglobin interacts specifically and reversibly with the red cell membrane. pH and ionic strength dependence of these interactions indicate their electrostatic nature. The anion transport protein band 3 has been implicated as the protein to which hemoglobin binds.Hemoglobin, aldolase and glyceraldehyde 3-phosphate dehydrogenase have a similar pH and ionic strength dependence in binding to 23K fragment. The three compete for the same amino-terminal 23 residue sequence region of band 3. The binding site is a highly acidic segment without any positive charge. We have recently determined the sequence of amino-terminal 23K fragment of band 3. There is a remarkable internal sequence homology between the first eleven and next eleven residues in this sequence region. Biophysical measurements have revealed that 23K is a tetramer under physiological conditions. The implications of this structure of 23K is discussed with respect to the interaction of band 3 with the red cell cytoskeleton.

Dosierung und Elimination von Dextran 40 bei Hämodialysepatienten

SummaryIn 24 patients on regular hemodialysis the serum levels and the half-life of dextran 40 were determined after single or repeated infusion of dextran 40 (Rheomacrodex®). One group of hemodialysis trainees had a dextran 40 half-life of 2237±447 min. In contrast, a second group, consisting of hospital dialysis patients, had a dextran 40 half-life of 4283±810 min, whereas patients with normal renal function had a half-life of 573±183 min. The difference in dextran half-life between the two groups of hemodialysis patients may be explained by the better residual ronal function of our hemodialysis trainees.During hemodialysis no change in serum dextran levels could be observed. Intermittent hemodialysis, also, had no influence on the exponential elimination of dextran over a period of 6.25 days. Since hemodialysis by itself has no effect upon dextran elimination, the dosage of dextran 40 has to be adjusted to the prolonged elimination time only, disregarding dialysis.After the fourth infusion of 50 g dextran 40 (twice a week 500 ml of 10% dextran 40) serum dextran levels exceeding 20 g/l and cutaneous bleeding were observed. To avoid these complications an initial saturation dose is suggested, followed by a maintenance dose adjusted to the impaired renal function.ZusammenfassungBei 24 Hämodialysepatienten wurden nach einmaliger und wiederholter Gabe von Dextran 40 (Rheomacrodex®) die Dextranspiegel im Serum bestimmt und daraus die Eliminationshalbwertzeiten errechnet. Diese betrugen bei Heimdialysepatienten 2237±447 min, bei Zentrumsdialysepatienten 4283±810 min und waren damit gegenüber nierengesunden Patienten (HWZ=573±183 min) auf das Fünf- bzw. Zehnfache verlängert. Die Unterschiede zwischen Heimdialyse- und Zentrumsdialysepatienten erklären sich durch die bessere Nierenrestfunktion der ersteren.Während der Hämodialyse kam es zu keinem Abfall der Dextranspiegel i.S. Weiterhin zeigte sich, daß die exponentielle Elimination von Dextran 40 über einen Beobachtungszeitraum von 6,25 Tagen durch die intermittierende Hämodialyse nicht beeinflußt wurde. Da keine nennenswerte Ausscheidung von Dextran 40 durch die Hämodialyse erfolgt, braucht die intermittierende Hämodialyse bei der Dosierung nicht berücksichtigt zu werden. Die Dosierung von Dextran 40 hat sich jedoch streng nach der verlängerten Eliminationshalbwertzeit zu richten.Die Gabe von 2 × 50 g Dextran 40 pro Woche (2 × 500 ml 10%iges Dextran 40) kann schon nach der 4. Infusion zu Dextranspiegeln i.S. über 20 g/l und zu Blutungen führen. Um diese Komplikationen zu vermeiden, wird eine von der Nierenfunktion unabhängige Initialdosis vorgeschlagen mit einer anschließenden Erhaltungsdosis, die sich nach der Nierenfunktion richtet.In 24 patients on regular hemodialysis the serum levels and the half-life of dextran 40 were determined after single or repeated infusion of dextran 40 (Rheomacrodex¿). One group of hemodialysis trainees had a dextran 40 half-life of 2237 +/- 447 min. In contrast, a second group, consisting of hospital dialysis patients, had a dextran 40 half-life of 4283 +/- 510 min, whereas patients with normal renal function had a half-life of 573 +/- 183 min. The difference in dextran half-life between the two groups of hemodialysis patients may be explained by the better residual renal function of our hemodialysis trainees. During hemodialysis no change in serum dextran levels could be observed. Intermitten hemodialysis, also, had no influence on the exponential elimination of dextran over a period of 6.25 days. Since hemodialysis by itself has no effect upon dextran elimination, the dosage fo dextran 40 has to be adjucted to the prolonged elimination time only, disregarding dialysis. After the fourth infusion of 50 g dextran 40 (twice a week 500 ml of 10% dextran 40) serum dextran levels exceeding 50 g/l and cutaneous bleeding were observed. To avoid these complications an initial saturation dose is suggested, followed by a maintenance dose adjusted to the impaired renal function.

[Second increase in plasma volume after single infusion of hydroxyethyl starch (author's transl)].

6 patients without evidence for renal, hepatic or pancreatic disease were treated with intravenous infusions of 500 ml hydroxyethyl starch (6%) over a period of 60 min. In the course of the infusion we observed an increase in plasma volume from 2.72 +/- 0.101 to 3.36 +/- 0.141. After 2 h plasma volume decreased to 3.02 +/- 0.101 but showed a second peak of 3.23 +/- 0.121 after 4 h (p less than 0.01). 24 h following infusion an increase in plasma volume of 4,8% was found as compared to preinfusion values. The second increase in plasma volume cannot be explained by the total concentration of hydroxyethyl starch since the latter decreased continuously. The increase in plasma volume was accompanied by a decrease in average molecular weight (-Mw and -Mn). It is suggested that serum amylase produces small osmotic active molecules by degradation of hydroxyethyl starch, thus leading to an increase in plasma volume. 12--24 h after the infusion of hydroxyethyl starch serum amylase was more than twice as high basal values. This is caused by the formation of a high molecular hydroxyethyl starch-amylase-complex which cannot be eliminated easily. When hydroxyethyl starch is given repeatedly to normovolemic patients, the second increase in plasma volume should be considered as a possible cause for acute hypervolemia. This is especially true for patients with myocardial insufficiency.Summary6 patients without evidence for renal, hepatic or pancreatic disease were treated with intravenous infusions of 500 ml hydroxyethyl starch (6%) over a period of 60 min. In the course of the infusion we observed an increase in plasma volume from 2.72±0.101 to 3.36±0.141. After 2h plasma volume decreased to 3.02±0.101 but showed a second peak of 3.23±0.121 after 4h (p<0.01). 24h following infusion an increase in plasma volume of 4,8% was found as compared to preinfusion values. The second increase in plasma volume cannot be explained by the total concentration of hydroxyethyl starch since the latter decreased continuously. The increase in plasma volume was accompanied by a decrease in average molecular weight004Dw and004Dn. It is suggested that serum amylase produces small osmotic active molecules by degradation of hydroxyethyl starch, thus leading to an increase in plasma volume. 12–24h after the infusion of hydroxyethyl starch serum amylase was more than twice as high basal values. This is caused by the formation of a high molecular hydroxyethyl starch-amylase-complex which cannot be eliminated easily. When hydroxyethyl starch is given repeatedly to normovolemic patients, the second increase in plasma volume should be considered as a possible cause for acute hypervolemia. This is especially true for patients with myocardial insufficiency.Zusammenfassung6 Patienten ohne Anhalt für eine Nieren-, Leber- oder Pankreaserkrankung erhielten innerhalb von 60 min 500 ml 6% Hydroxyäthylstärke 450/0,7. Während der Infusion stieg das Plasmavolumen von 2,72±0,101 auf 3,36±0,141 an, fiel in der 2. Stunde wieder auf 3,02±0,101 ab und erreichte nach der 4. Stunde einen zweiten Gipfel von 3,23±0,121 (p<0,01). Nach 24h lag das Plasmavolumen noch 4,8% über dem Ausgangswert. Dieser „Volumenzweiteffekt“ ist nicht durch die Hydroxyäthylstärke-Gesamtkonzentration zu erklären, da diese kontinuierlich exponentiell abfiel. Mit dem erneuten Volumenanstieg nach der 4. Stunde ging eine Abnahme des Zahlenmittels004Dn und des Gewichtsmittels004Dw einher. Dies spricht dafür, daß infolge der Fraktionierung durch die Serumamylase vermehrt osmotisch aktive Hydroxyäthylstärke-Moleküle entstehen, die zu einer Zunahme des Plasmavolumens führen. 12–24h nach Infusionsbeginn stieg die Serumamylase auf über das Doppelte ihres Ausgangswertes an. Ursache dieser Hyperamylasämieist die Bildung eines Hydroxyäthylstärke-Amylase-Komplexes, der infolge seiner Größe nur schwer eliminiert wird. Um eine Volumenüberlastung zu vermeiden, muß bei mehrmaliger Infusion von Hydroxyäthylstärke der Volumenzweiteffekt berücksichtigt werden, besonders bei Patienten nit eingeschränkter kardialer Leistungsbreite.

Volumenzweiteffekt nach einmaliger Infusion von Hydroxyäthylstärke

6 Patienten ohne Anhalt fur eine Nieren-, Leber- oder Pankreaserkrankung erhielten innerhalb von 60 min 500 ml 6% Hydroxyathylstarke 450/0,7. Wahrend der Infusion stieg das Plasmavolumen von 2,72±0,101 auf 3,36±0,141 an, fiel in der 2. Stunde wieder auf 3,02±0,101 ab und erreichte nach der 4. Stunde einen zweiten Gipfel von 3,23±0,121 (p<0,01). Nach 24h lag das Plasmavolumen noch 4,8% uber dem Ausgangswert. Dieser „Volumenzweiteffekt“ ist nicht durch die Hydroxyathylstarke-Gesamtkonzentration zu erklaren, da diese kontinuierlich exponentiell abfiel. Mit dem erneuten Volumenanstieg nach der 4. Stunde ging eine Abnahme des Zahlenmittels004Dn und des Gewichtsmittels004Dw einher. Dies spricht dafur, das infolge der Fraktionierung durch die Serumamylase vermehrt osmotisch aktive Hydroxyathylstarke-Molekule entstehen, die zu einer Zunahme des Plasmavolumens fuhren. 12–24h nach Infusionsbeginn stieg die Serumamylase auf uber das Doppelte ihres Ausgangswertes an. Ursache dieser Hyperamylasamieist die Bildung eines Hydroxyathylstarke-Amylase-Komplexes, der infolge seiner Grose nur schwer eliminiert wird. Um eine Volumenuberlastung zu vermeiden, mus bei mehrmaliger Infusion von Hydroxyathylstarke der Volumenzweiteffekt berucksichtigt werden, besonders bei Patienten nit eingeschrankter kardialer Leistungsbreite.

Side-Effects of High-Dose Dicloxacillin Therapy

The limiting toxic factor in high-dose penicillin therapy seems to be the effect on the central nervous system. In comparison with other semisynthetic penicillins dicloxacillin is the most neurotoxic in rabbits, as previous studies have shown (11). In rabbits neurotoxic serum levels also produce hemolysis. Cloxacillin, oxacillin and carbenicillin showed to be less neurotoxic and did not induce hemolysis. The present study was undertaken to determine whether in high-dose dicloxacillin therapy hemolysis is likely in man and is, therefore, of clinical importance.